# Polyketides via Redox-Triggered Alcohol C-H Functionalization

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $80,515

## Abstract

Polyketides are used more frequently in human medicine than any other class of secondary
metabolites, and comprise roughly 20% of top-selling small-molecule drugs. Despite their
importance: (a) All polyketides used in human medicine are derived from soil bacteria and are
prepared via fermentation or semi-synthesis (notwithstanding eribulin), (b) <5% of soil bacteria
are amenable to culture, many phyla have eluded culture, and the few bacteria amenable to
culture express <10% of their biosynthetic genes, (c) although marine polyketides possess an
astonishing array of biological activities, commercial fermentation processes involving marine
bacteria (which are often symbionts) remain exceptionally uncommon. De novo chemical
synthesis potentially offers entry to otherwise inaccessible polyketides and their congeners, yet
current synthetic methods often do not avail sufficiently concise routes for large scale production.
To overcome this challenge, our laboratory has pioneered a broad, new family of catalytic
methods for the direct stereo- and site-selective conversion of lower alcohols to higher alcohols.
As documented in numerous total syntheses, these methods streamline polyketide construction,
allowing the target compounds to be prepared in significantly fewer steps than previously
possible.
In the proposed funding period, 3 specific aims are proposed: (a) Total syntheses of the type I
polyketides neaumycin B and gladiolin will be pursued using our catalytic methods. Neaumycin B
is a femtomolar inhibitor of U87 human glioblastoma. Gladiolin displays potent, selective activity
against M. tuberculosis strains that are resistant to the frontline antibiotics isoniazid and
rifampicin. (b) The type II polyketide antibiotics formicamycins G, H and J, arenimycin A and
analogues of viridicatumtoxin will be prepared using our catalytic methods. Antibacterial
properties of these compounds will be evaluated in collaboration with Prof. Barrie Wilkinson
and Prof. Jean Chmielewski. (c) Ruthenium-catalyzed reactions relevant to polyketide
construction (allylation, crotylation, propargylation, etc.) will be developed. Optimization of these
methods will be assisted by computational studies performed by Prof. Kuo-Wei Huang. Thus,
our studies advance an integrated program in which methodological innovation informs
synthesis, and synthesis informs medicinal chemistry.

## Key facts

- **NIH application ID:** 11079388
- **Project number:** 3R01GM093905-14S1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** MICHAEL J KRISCHE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $80,515
- **Award type:** 3
- **Project period:** 2011-05-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11079388

## Citation

> US National Institutes of Health, RePORTER application 11079388, Polyketides via Redox-Triggered Alcohol C-H Functionalization (3R01GM093905-14S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11079388. Licensed CC0.

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